Myeloid-derived suppressor cells (MDSCs) is a recently characterized population of cells that expands during cancer, infection, inflammation, and trauma. MDSCs display a remarkable ability to suppress T cell-mediated immunity by multiple mechanisms including production of arginase 1, reactive oxygen species, nitric oxide, and induction of regulatory T cells. MDSCs represent an important regulatory feedback immune mechanism preventing exaggerated chronic inflammation in the context of various diseases. HIV-1 infection is characterized by chronic activation and rapid turnover of CD4+ and CD8+ T cells. Recently obtained evidence suggests that HIV-1 infection is associated with chronic inflammation in the gastrointestinal mucosal tissue and a translocation of microbial products to the systemic compartment where they contribute to T cell activation. Activation-driven exhaustion of CD4+ T cell regenerative capability eventually leads to the collapse of CD4+ T cell homeostasis. Precise characterization of the mechanisms underlying chronic T cell activation is central to the understanding of HIV-1 pathogenesis. It would be expected that chronic immune activation associated with HIV-1 infection would result in a significant expansion of MDSC population as observed in other viral and bacterial infections. Surprisingly, our preliminary data demonstrate that the frequency of circulating MDSCs is significantly reduced in HIV-1-infected patients, particularly patients not treated with highly active anti-retroviral therapy (HAART). Absence of this important regulatory population that normally restricts harmful immune activation may significantly contribute to the uncontrolled chronic inflammation in the systemic compartment and intestinal mucosal tissue and to the high incidence of autoimmune disorders observed in HIV-1-infected individuals. We will address the role of MDSCs in HIV-1 infection in three specific aims: 1) Determine whether the frequency of MDSCs is reduced in the blood and intestinal tissue of HIV-1-infected individuals;2) Determine whether MDSCs can be directly infected with HIV-1;and 3) Determine whether MDSCs in HIV-1- infected patients preserve their immunosuppressive activity. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients. PUBLIC HEALTH RELEVANCE: In this application we present a novel observation that HIV-1 infection is associated with a severe depletion of myeloid-derived suppressor cells (MDSCs) and hypothesize that the absence of this important immunoregulatory population significantly contributes to the chronic immune activation resulting in the gradual decline of CD4+ T cells. Precise characterization of mechanisms underlying chronic T cell activation is central to our understanding of HIV-1 pathogenesis. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients.